Learning from cancer: Using D-lactate for therapeutic immunosuppression

Accumulation of lactic acid in the tumor microenvironment contributes to local immunosuppressive conditions that weaken anti-tumor immunity. In mammals including humans, lactate is present almost entirely as the L-lactate optical isomer. We hypothesized that D-lactate could have similar immune modulatory effects that maybe exploited for therapeutic immunosuppression. 5–40 mM of added sodium D- and L-lactate caused marked impairment of murine, and human, CD4 and CD8 T cell proliferation in vitro, with stronger effects of D-lactate than L-lactate. Neither D- nor L-lactate affected cell viability or apoptosis. Adding 20 mM D-lactate to CD4 + Foxp3 − T cells under polarizing conditions increased Foxp3 + induced regulatory T cell (iTreg) formation by 46.2 ±31.5% (P 6 conventional T cells, with or without 1.25×10 5 Tregs, into Rag1 −/− mice, treated each group with 90 mmol/kg/d D-lactate or NaCl for 5 days. After 7 days, T cell proliferation was reduced by 62.1% using D-lactate treatment (P + Treg formation was increased in D-lactate (14.9 ±3.4%) vs. NaCl (10.6 ±2.3%) treated animals (P